An influenza hemagglutinin stem nanoparticle vaccine induces cross-group 1 neutralizing antibodies in healthy adults
Authors: Alicia T. Widge, Amelia R. Hofstetter, Katherine V. Houser, Seemal F. Awan, Grace L. Chen, Maria C. Burgos Florez, Nina M. Berkowitz, Floreliz Mendoza, Cynthia S. Hendel, LaSonji A. Holman, Ingelise J. Gordon, Preeti Apte, C. Jason Liang, Martin R. Gaudinski, Emily E. Coates, Larisa Strom, Diane Wycuff, Sandra Vazquez, Judy A. Stein, Jason G. Gall, William C. Adams, Kevin Carlton, Rebecca A. Gillespie, Adrian Creanga, Michelle C. Crank, Sarah F. Andrews, Mike Castro, Leonid A. Serebryannyy, Sandeep R. Narpala, Christian Hatcher, Bob C. Lin, Sarah O’Connell, Alec W. Freyn, Victoria C. Rosado, Raffael Nachbagauer, Peter Palese, Masaru Kanekiyo, Adrian B. McDermott, Richard A. Koup, Lesia K. Dropulic, Barney S. Graham, John R. Mascola, Julie E. Ledgerwood, Allison Beck, Joseph Casazza, Christopher L. Case, John Misasi, Abidemi O. Ola, Karen Parker, Richard Wu, Pamela Costner, Jamie Saunders, Laura Novik, William Whalen, Xiaolin Wang, Aba Mensima Eshun, Jennifer Cunningham, Anita Arthur, Morgan Anderson, Justine Jones, Brenda Larkin, Thuy Nguyen, Sandra Sitar, Lam Le, Iris Pittman, Olga Vasilenko, Galina Yamshchikov, Ro Shauna Rothwell, Eugenia Burch, Olga Trofymenko, Sarah Plummer, Catina Evans, Cora Trelles Cartagena, Renunda Hicks, LaShawn Requilman, Pernell Williams, Carmencita Graves, Shinyi Telscher, Gabriela Albright, Jessica Bahorich, Sashikanth Banappagari, Michael Bender, Alegria T. Caringal, Juliane Carvalho, Rajoshi Chaudhuri, Mythili Chintamani, Jonathan Cooper, Jacob Demirji, Tracey Dinh, Gelu Dobrescu, Alvenne Goh, Deepika Gollapudi, Raju Gottumukkala, Daniel Gowetski, Janel Holland-Linn, Jin Sung Hong, Joe Horwitz, Vera Ivleva, Lisa Kueltzo, Nadji Lambert, Alaina LaPanse, Heather Lawlor, Kristin Leach, James Lee, Paula Lei, Yile Li, Jie (Amy) Liu, Slobodanka Manceva, Aakash Patel, Rahul Ragunathan, Lori Romaine, Erwin Rosales, Nikki Schneck, William Shadrick, Andrew Shaddeau, Sudesh Upadhyay, Karen Vickery, Xiangchun (Eric) Wang, Xin Wang, Jack Yang, Rong (Sylvie) Yang, Yanhong Yang, Yansong Yi, Weidong Zhao, Zhong Zhao
Journal: Science Translational Medicine (2023)

Influenza vaccines could be improved by platforms inducing cross-reactive immunity. Immunodominance of the influenza hemagglutinin (HA) head in currently licensed vaccines impedes induction of cross-reactive neutralizing stem-directed antibodies. A vaccine without the variable HA head domain has the potential to focus the immune response on the conserved HA stem. This first-in-human dose-escalation open-label phase 1 clinical trial (NCT03814720) tested an HA stabilized stem ferritin nanoparticle vaccine (H1ssF) based on the H1 HA stem of A/New Caledonia/20/1999. Fifty-two healthy adults aged 18 to 70 years old enrolled to receive either 20 μg of H1ssF once ( n = 5) or 60 μg of H1ssF twice ( n = 47) with a prime-boost interval of 16 weeks. Thirty-five (74%) 60-μg dose participants received the boost, whereas 11 (23%) boost vaccinations were missed because of public health restrictions in the early stages of the COVID-19 pandemic. The primary objective of this trial was to evaluate the safety and tolerability of H1ssF, and the secondary objective was to evaluate antibody responses after vaccination. H1ssF was safe and well tolerated, with mild solicited local and systemic reactogenicity. The most common symptoms included pain or tenderness at the injection site ( n = 10, 19%), headache ( n = 10, 19%), and malaise ( n = 6, 12%). We found that H1ssF elicited cross-reactive neutralizing antibodies against the conserved HA stem of group 1 influenza viruses, despite previous H1 subtype head-specific immunity. These responses were durable, with neutralizing antibodies observed more than 1 year after vaccination. Our results support this platform as a step forward in the development of a universal influenza vaccine.